The optimal physical and chemical requirements for synthesis of nanoformulated antiretroviral drugs nanoART) into phospholipid coated nanoparticles and block copolymer micelles will be developed. Manufacture will be performed to facilitate cell uptake and slow release and pharmacokinetic (PK) studies (Project 2, H. Gendelman) and for PK and antiretroviral studies as performed in infected animals (Project 3, H. Fox). Although integration between formulation synthesis; in vitro testing for cytotoxicity, nanoparticle encased drug uptake and release; and in vivo rodent PK has been achieved, optimization of synthesis for inevitable clinical use will require continued integration and works. We posit that this will be realized with none or limited cell and tissue toxicities. A principal focus for this project is to consistently achieve high consistent antiretroviral drug levels in virus-target tissues including the lymphoid and central nervous systems. To address this, the project seeks a robust and scalable procedure for preparation of nanoART formulations with optimal size range, surface coating and colloidal stability. This would maximize circulating monocyte uptake and delivery to sites of active viral growth. Five drugs are proposed that include efavirenz, ritonavir, indinavir, lopinavir and atazanavir of which three will be used in large animal tests. The precipitation, homogenization, wet milling and micelle solubilization techniques will be used to prepare nanoART with adequate stability, both chemical and physical, for sufficient drug loading, appropriate osmolarity, viscosity and sterility. This will be performed in full compliance with United States Pharmacopeia practices. The best nanoART formulations, determined by bioimaging (Core B, M. Boska) and appropriate PK support (Core C, C. Fletcher) will be scaled-up for animal testing using Core A, H. Gendelman as a development and logistical guide. The strengths of this project rest in multiple areas including the now extensive new preliminary data, the expertise of the investigators, the research environment, and the clear cooperation and integration made between the cores and the projects. Excitement surrounds the integration of multiple scientific approaches to derive clinical benefit in a set need for substance abusers.